Copper(I)-catalyzed boryl substitution of unactivated alkyl halides

Article abstract of DOI:10.1021/ol203413w

Borylation of alkyl halides with diboron proceeded in the presence of a copper(I)/Xantphos catalyst and a stoichiometric amount of K(O-t-Bu) base. The boryl substitution proceeded with normal and secondary alkyl chlorides, bromides, and iodides, but alkyl sulfonates did not react. Menthyl halides afforded the corresponding borylation product with excellent diastereoselectivity, whereas (R)-2-bromo-5-phenylpentane gave a racemic product. Reaction with cyclopropylmethyl bromide resulted in ring-opening products, suggesting the reaction involves a radical pathway.

Full text of DOI:10.1021/ol203413w

ORGANIC
LETTERS
2012
Vol. 14, No. 3
890–893
Copper(I)-Catalyzed Boryl Substitution of
Unactivated Alkyl Halides
Hajime Ito* and Koji Kubota
Division of Chemical Process Engineering, Graduate School of Engineering,
Hokkaido University, Sapporo, Hokkaido 060-8628, Japan
hajito@eng.hokudai.ac.jp
Received December 21, 2011
ABSTRACT
Borylation of alkyl halides with diboron proceeded in the presence of a copper(I)/Xantphos catalyst and a stoichiometric amount of K(O-t-Bu) base.
The boryl substitution proceeded with normal and secondary alkyl chlorides, bromides, and iodides, but alkyl sulfonates did not react. Menthyl
halides afforded the corresponding borylation product with excellent diastereoselectivity, whereas (R)-2-bromo-5-phenylpentane gave a racemic
product. Reaction with cyclopropylmethyl bromide resulted in ring-opening products, suggesting the reaction involves a radical pathway.
Organoboron compounds are indispensable synthetic
reagents in organic synthesis; much effort has therefore
been devoted to the development of an efficient synthesis
of organoborons.1ꢀ8 Although many excellent procedures
have been reported, boryl substitution of alkyl halides is
still challenging. In conventional procedures for organo-
boron synthesis, alkyl halides are the starting materials for
the organometallic nucleophiles, such as Grignard or
organolithium reagents, which react with boron electro-
philes. This procedure has significant limitations, espe-
cially in the presence of the functional groups often found
in structurally complex molecules. Direct borylation of
alkyl halides should be quite promising in this respect.
Yamashita and Nozaki recently created a boryllithium
(1) (a) Boronic Acids: Preparation and Applications in Organic Synthe-
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Organoboranes; Springer: Berlin, 1995. (c) Boron Compounds, Science of
Syntheses; Kaufmann, D., Ed.; Georg Thieme Verlag: Stuttgart, 2005; Vol. 6.
(d) Chemler, S. R.; Roush, R. W. In Modern Carbonyl Chemistry; Otera,
J., Ed.; Wiley-VCH: Weinheim, 2000; pp 403ꢀ490. (e) Miyaura, N;
Yamamoto, Y. In Comprehensive Organometallic Chemistry III; Crabtree,
R. H., Mingos, M. P.; Elsevier: Amsterdam, 2007; Vol. 9, pp 146ꢀ244.
(2) For selected reviews of transition-metal-catalyzed reactions, see:
(a) Crudden, C. M.; Edwards, D. Chem.;Eur. J. 2003, 4695.
(b) Miyaura, N. Bull. Chem. Soc. Jpn. 2008, 81, 1535. (c) Dang, L.;
Lin, Z. Y.; Marder, T. B. Chem. Commun. 2009, 3987.
(5) For selected examples of copper(I)-catalyzed reactions of R,
β-unsaturated carbonyl compounds, see: (a) Takahashi, K.; Ishiyama, T.;
Miyaura, N. Chem. Lett. 2000, 982. (b) Takahashi, K.; Ishiyama, T.;
Miyaura, N. J. Organomet. Chem. 2001, 625, 47. (c) Mun, S.; Lee, J.;
Yun, J. Org. Lett. 2006, 8, 4887. (d) Lee, J.; Yun, J. Angew. Chem., Int.
Ed. 2008, 47, 145. (e) Bonet, A.; Lillo, V.; Ramirez, J.; Diaz-Requejo, M.;
Fernandez, E. Org. Biomol. Chem. 2009, 7, 1533. (f) Chea, H.; Sim, H.;
Yun, J. Adv. Synth. Catal. 2009, 351, 855. (g) Chen, I.-H.; Yin, L.; Itano,
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3478. See also: ref 4a.
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(3) (a) Segawa, Y.; Yamashita, M.; Nozaki, K. Science 2006, 314,
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Chem. Soc. Jpn. 2011, 84, 983.
(4) For copper(I)-catalyzed reaction of diboron developed by our
group, see: (a) Ito, H.; Yamanaka, H.; Tateiwa, J.; Hosomi, A.
Tetrahedron Lett. 2000, 41, 6821. (b) Ito, H.; Kawakami, C.; Sawamura,
M. J. Am. Chem. Soc. 2005, 127, 16034. (c) Ito, H.; Ito, S.; Sasaki, Y.;
Matsuura, K.; Sawamura, M. J. Am. Chem. Soc. 2007, 129, 14856.
(d) Ito, H.; Kosaka, Y.; Nonoyama, K.; Sasaki, Y.; Sawamura, M.
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Nat. Chem. 2010, 2, 972. (g) Ito, H.; Okura, T.;Matsuura, K.;Sawamura,
M. Angew. Chem., Int. Ed. 2010, 49, 560. (h) Ito, H.; Toyoda, T.;
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C. M.; Sawamura, M.; Ito, H. J. Am. Chem. Soc. 2010, 132, 1226.
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r
10.1021/ol203413w
Published on Web 01/19/2012
2012 American Chemical Society

species by introducing significant steric hindrance
around the boron atom.3 Although this species has
enough nucleophilicity to react with unactivated alkyl
halides, this elaborate reaction is not suitable for many
common organic syntheses. Miyaura and Marder also
reported boryl substitutions of activated alkyl halides
such as allyl and benzyl chlorides; however, there are
no general borylation procedures for unactivated alkyl
halides.1,5a,5b,7 We report here the first practical meth-
od for boryl substitution that is applicable to a broad
range of alkyl halides with various functional groups,
offering a direct umpolung pathway for conventional
reactions based on carbon nucleophiles generated
from alkyl halides.
This reaction was then evaluated for various alkyl
halides, as summarized in Table 2. Unactivated primary
and secondary alkyl halides were converted to the corre-
sponding alkylboronates in good yield (entries 1ꢀ6). The
effects of the leaving group were investigated with cyclo-
hexyl substrates (entries 2ꢀ5). Reaction of cyclohexyl
bromide 1d gave the borylation product 3c in the highest
yield, with a short reaction time (91%, 5 h), among
cyclohexyl chloride 1c and iodide 1e (72%, 18 h; 79%,
Table 1. Studies of Reaction Conditions for Copper(I)-Cata-
lyzed Boryl Substitution of Alkyl Halide 1aa
Recent advances in copper(I)-catalyzed reactions with
diboron derivatives4ꢀ8 enableintroductionofboryl groups
into various organic electrophiles such as R,β-unsaturated
carbonyl compounds,4a,5 allylic esters,4b,c,f,g,6 aryl halides,7
allyl and benzyl halides,5a,b,7 and other substrates.4d,hꢀk,8
We did not anticipate that unactivated alkyl halides could
afford boron compounds by copper(I)-catalyzed boryla-
tion because we previously found that alkyl sulfonates,
which are good substrates for nucleophilic substitutions,
were resistant to direct boryl substitution.4h,9
In the course of our study, we accidentally found that
an alkyl halide reacted with a diboron compound to
produce the corresponding alkylboronate in the pre-
sence of a copper(I) catalyst, which is very similar to
those we previously reported.4b,h As shown in Table 1,
entry 1, the reaction between 2-phenylethyl bromide 1a
and bis(pinacolato)diboron 2 proceeded smoothly in
the presence of a CuCl/Xantphos catalyst (3 mol %)
and a stoichiometric amount of K(O-t-Bu) base (1.0
equiv). The reaction was complete within 4 h at room
temperature and produced the corresponding boron-
ate 3a in high yield (94%) without any side-product
detection (Table 1, entry 1). This catalysis requires a
K(O-t-Bu) base, a copper(I) salt, and a ligand for the
reaction to proceed (entries 2ꢀ4). Xantphos provided
the best result among the phosphine ligands tested; the
reactions with PPh3, dppe, dppp, dppb, and dppf were
slow and incomplete, resulting in moderate yields of
the product, even after long reaction times (entries
5ꢀ9). Use of a copper(I)/NHC (NHC: N-heterocyclic
carbene) catalyst gave a much slower initial reaction
rate (entry 10). When a catalytic or stoichiometric
amount of Cu(O-t-Bu) was used instead of a CuCl/
K(O-t-Bu) combination, only trace amounts of the
product were observed (entries 11 and 12). CuI, CuCN,
and Cu(OAc)2 can be used, but longer reaction times
were required (entries 13ꢀ15).10 A lower catalyst load-
ing of 1 mol % also gave an excellent result (96%, 4 h,
entry 16).
a Conditions: 1a (0.5 mmol), CuX (0.015 mmol), ligand (0.015 mmol),
K(O-t-Bu)/THF (1.0 M, 0.5 mL), 2 (0.6 mmol). b Yield was deter-
mined by GC analysis of crude mixture with an internal stan-
dard. c CuClIPr: chloro[1,3-bis(2,6-diisopropylphenyl)-imidazole-2-ylidene]
copper(I).
48 h, respectively). In contrast, cyclohexyl mesylate 1f did
not react (entry 5). This lack of reactivity is consistent with
our previous studies of related mesylate substrates.4h The
reactions of tertiary alkyl halides 1h and 1i were quite
sluggish (entries 7 and 8). An activated alkyl halide, benzyl
bromide 1j, also gave the desired product in moderate
yield, accompanied by a small amount of a homocoupling
side product (1,2-diphenylethane, 9%).7 Thisreaction pro-
ceeded in the presence of various functional groups;
acetal (1k), ester (1l), silyl ether (1m), and sulfonate
(1n) were compatible under these reaction conditions
(entries 9ꢀ14). Alkylboronates bearing a β-alkoxy
group were not accessible by Grignard or organo-
lithium methods because the corresponding organo-
metallic compounds with a β-alkoxy group could
not be easily prepared owing to facile β-alkoxy
elimination. This method enables direct conversion
of alkyl halide 1o to 3o (entry 14). Reactions of 1,
1- and 1,3-dibromo compounds proceeded smoothly to
(9) We reported that a 4-silyl-3-butenyl methanesulfonate gave a
cyclobutylboronate product under copper(I)-catalyzed conditions in the
presence of diboron, in which no simple substitution product was
detected.
(10) Copper(II) salt was most probably reduced to copper(I) at the
initial step of the catalysis. See also ref 6a.
Org. Lett., Vol. 14, No. 3, 2012
891

Table 2. Copper(I)-Catalyzed Boryl Substitution of Alkyl
Halidesa
Scheme 1. Attempts of Copper(I)-Catalyzed Hydroboration of
Alkenes with Diboron 2
Scheme 2. Experiments for Exclusion of Elimination/Hydro-
boration Pathway of 1s and 1t
a Conditions: 1(0.5 mmol), CuCl (0.015 mmol), Xantphos (0.015 mmol),
K(O-t-Bu)/THF (1.0 M, 0.5 mL), 2 (0.6 mmol), room temperature. b Iso-
1
lated yield. Values in parentheses are the yields determined by H NMR
(1S,2R,5R)-menthyl chloride 1r and (1S,2S,4R)-neomenthyl
bromide 1s (entries 16 and 17, 85% and 81%, respectively).
analysis of the crude mixture. c 5 mol % of catalyst and 1.2 equiv of K
(O-t-Bu) were used. d Reaction was conducted at 40 °C with 15 mol % of
catalyst and 2.2 equiv of 2. e 2.0 equiv of K(O-t-Bu) was used. f 10 mol % of
catalyst and 2.0 equiv of 2 were used.
(11) For stereochemistry of alkylation with copper(I) reagents, see:
(a) Whitesides, G. M.; Fischer, W. F.; San Filippo, J.; Bashe, R. W.;
House, H. O. J. Am. Chem. Soc. 1969, 91, 4871. (b) Johnson, C. R.;
Dutra, G. A. J. Am. Chem. Soc. 1973, 95, 7777. (c) Lipshutz, B.;
Wilhelm, R. S. J. Am. Chem. Soc. 1982, 104, 4696. (d) Mori, S.;
Nakamura, E.; Morokuma, K. J. Am. Chem. Soc. 2000, 122, 7294.
(e) Terao, J.; Todo, H.; Begum, S. A.; Kuniyasu, H.; Kambe, N. Angew.
Chem., Int. Ed. 2007, 46, 2086.
produce the corresponding bis-boryl products (entries
14 and 15). (1R,2R,4R)-Menthyl boronate 3r was synthe-
sized with excellent diastereoselectivity (>99:1) from both
892
Org. Lett., Vol. 14, No. 3, 2012

The reaction of the optically active secondary alkyl
halide (R)-1t afforded the racemic product 3t (entry 19).
These results indicate that the stereocenter originating
from the chiral C(sp3)ꢀX bond undergoes rapid inter-
conversion of configuration during the reaction. This
may cause epimerization to a thermodynamically
stable product (entries 17 and 18) and complete race-
mization (entry 19). This is quite different from the
results of our previous studies on copper(I)-catalyzed
substitution of acyclic allylic carbonates with diboron,
where the anti-SN20 reaction proceeded with high
stereospecificity.4b,11
3-Butenylboronate 4 (18%) and bis-boryl product 5
(30%), which could be derived from 4 through further
borylation of the terminal double bond, were found in
the reaction mixture, but the simple boryl substitution
product 3u was not detected. The formation of the
ring-opening products suggests that this reaction could
include a radical pathway; this assumption is not incon-
sistent with the stereochemical outcomes observed in
entries 17ꢀ19, Table 2.12,13 However, further studies are
needed for a full explanation of the reaction mechanism.
This reaction does not include a base-promoted
elimination/alkene hydroboration pathway. The following
experiments exclude this mechanism. (1) Alkenes did not
undergo hydroboration under the reaction conditions
presented in Tables 1 and 2 (Schemes 1 and 2). (2) Base-
promoted elimination of alkyl halides proceeded quickly in
the presence of t-BuOK; however, by addition of 2, base-
promoted elimination was completely inhibited (Scheme 2).
Complexation of t-BuOK and Lewis acidic 2 would reduce
the basicity of t-BuOK siginificantly. (3) Our boryl sub-
stitution of secondary alkyl halides was regiospecific
(Table 2, entries 6, 17, 18, and 19). However, elimination
products of secondary alkyl halides should give regioi-
somers in terms of the double bond (Scheme 2). It is
difficult to assume product convergence in hydroboration
of regioisomeric alkenes. In addition, the base-promoted
elimination products from 1s and 1t did not undergo
hydroboration under the conditions for our copper(I)-
catalyzed boryl substitution of alkyl halides (Scheme 2).
To probe the reaction mechanism further, we also
carried out the copper(I)-catalyzed borylation of cyclo-
propylmethyl bromide (1u), as illustrated in Scheme 3.
Scheme 3. Copper(I)/Xantphos-Catalyzed Borylation of Cy-
clopropylmethyl Bromide (1u)
In summary, we have developed a novel copper(I)-
catalyzed reaction as the first practical procedure for boryl
substitution of unactivated alkyl halides. This reaction
offers a direct umpolung pathway for the conventional
carbon nucleophile method and has high functional group
compatibility and interesting stereochemical-controlling
properties. We believe that this procedure will be a power-
ful synthetic method for a broad range of alkylboronates,
including those that could not be synthesized by previous
methods.
Acknowledgment. This work was financially supported
by the Funding Program for Next Generation World-
Leading Researchers (NEXT Program, No. G002) from
the Japan Society for the Promotion of Science (JSPS).
(12) For radical pathways in reactions of lithium organocuprate with
alkyl halides, see: (a) Ashby, E. C.; DePriest, R. N.; Tuncay, A.;
Srivastava, S. Tetrahedron Lett. 1982, 23, 5251. (b) Ashby, E. C.; Coleman,
D. J. Org. Chem. 1987, 52, 4554.
(13) For rapid isomerization of a cyclopropyl radical to the butenyl
radical, see: (a) Maillard, B.; Forrest, D.; Ingold, K. U. J. Am. Chem.
Soc. 1976, 98, 7024. (b) Griller, D.; Ingold, K. U. Acc. Chem. Res. 1980,
13, 317.
(14) During submission process of this paper, a similar reaction with
CuCl/PPh3/base was published. Yang, C.-T.; Zhang, Z.-Q.; Tajuddin,
H.; Wu, C.-C.; Liang, J.; Liu, J.-H.; Fu, Y.; Czyzewska, M.; Steel, P. G.;
Marder, T. B.; Liu, L. Angew. Chem., Int. Ed. 2012, 51, 528.
Supporting Information Available. Details of experi-
1
mental procedure, H and 13C spectra. This material is
available free of charge via the Internet at http://pubs.
acs.org.
Org. Lett., Vol. 14, No. 3, 2012
893